Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain

ABSTRACT

Methods of making and using racemic and optically pure metabolites of sibutramine, and pharmaceutically acceptable salts, solvates, and clathrates thereof, are disclosed. Pharmaceutical compositions and dosage forms are also disclosed which comprise a dopamine reuptake inhibitor, such as a racemic or optically pure sibutramine metabolite, and optionally an additional pharmacologically active compound.

This application is a continuation-in-part of U.S. application Ser. No.09/372,158, filed Aug. 11, 1999, the entirety of which is incorporatedherein by reference.

1. FIELD OF THE INVENTION

The invention relates to compositions comprising dopamine reuptakeinhibitors, including racemic and optically pure metabolites ofsibutramine, and to methods of making and using the same.

2. BACKGROUND OF THE INVENTION

Sibutramine, chemically named[N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine, isa neuronal monoamine reuptake inhibitor which was originally disclosedin U.S. Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits thereuptake of norepinephrine and, to a lesser extent, serotonin anddopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol.Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611(1989).

Racemic sibutramine is sold as a hydrochloride monohydrate under thetradename MERIDIA®, and is indicated for the treatment of obesity.Physician's Desk Reference® 1494-1498 (53^(rd) ed., 1999). The treatmentof obesity using racemic sibutramine is disclosed, for example, in U.S.Pat. No. 5,436,272.

Sibutramine appears to have been extensively studied, and reportedlycould be used in the treatment of a variety of disorders. For example,U.S. Pat. Nos. 4,552,828, 4,746,680, 4,806,570, and 4,929,629 disclosemethods of treating depression using racemic sibutramine, and U.S. Pat.Nos. 4,871,774 and 4,939,175 disclose methods of treating Parkinson'sdisease and senile dementia, respectively, using racemic sibutramine.Other uses of sibutramine are disclosed by PCT publications WO 95/20949,WO 95/21615, WO 98/11884, and WO 98/13033. Further, the optically pureentantiomers of sibutramine have been considered for development. Forexample, PCT publications WO 94/00047 and 94/00114 disclose methods oftreating depression and related disorders using the (+)-and(−)-enantiomers of sibutramine, respectively.

Sibutramine is rapidly absorbed from the gastrointestinal tractfollowing oral administration and undergoes an extensive first-passmetabolism that yields the primary metabolites, desmethylsibutramine anddidesmethylsibutramine, shown below.

It has been reported that desmethylsibutramine anddidesmethylsibutramine are more potent in vitro noradrenaline and5-hydroxytryptamine (5HT; serotonin) reuptake inhibitors thansibutramine. Stock, M. J., Int'l J. Obesity, 21(Supp. 1):S25-S29 (1997).It has further been reported, however, that sibutramine and itsmetabolites have negligible affinities for a wide range ofneurotransmitter receptors, including serotonergic (5-HT₁, 5-HT_(1A),5-HT_(1D), 5-HT_(2A), 5-HT_(2C)), adrenergic, dopaminergic, muscarinic,histaminergic, glutamate, and benzodiazepine receptors. Id.

Sibutramine has a variety of adverse effects. See, e.g., Physician'sDesk Reference® 1494-1498 (53^(rd) ed., 1999). Coupled with the reportedbenefits and therapeutic insufficiencies of sibutramine, this fact hasencouraged the discovery of compounds and compositions that can be usedin the treatment or prevention of disorders such as, but not limited to,erectile dysfunction, affective disorders, weight gain or obesity,cerebral function disorders, pain, obsessive-compulsive disorder,substance abuse, chronic disorders, anxiety, eating disorders,migraines, and incontinence. In particular, compounds and compositionsare desired that can be used for the treatment and prevention of suchdisorders and conditions while incurring fewer of the adverse effectsassociated with sibutramine.

3. SUMMARY OF THE INVENTION

This invention encompasses methods, pharmaceutical compositions, anddosage forms for the treatment and prevention of disorders that areameliorated by the inhibition of neuronal monoamine uptake in mammals,including humans. Examples of such disorders include, but are notlimited to, erectile dysfunction, affective disorders, weight gain orobesity, cerebral function disorders, pain, obsessive-compulsivedisorder, substance abuse, chronic disorders, anxiety, eating disorders,migraines, and incontinence. The methods of the invention compriseadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof.

This invention also encompasses a method of treating or preventingerectile dysfunction which comprises adjunctively administering to apatient in need of such treatment or prevention therapeutically orprophylactically effective amounts of a dopamine reuptake inhibitor anda 5-HT₃ antagonist.

Pharmaceutical compositions of the invention comprise a therapeuticallyor prophylactically effective amount of a neuronal monoamine reuptakeinhibitor. Preferred neuronal monoamine reuptake inhibitors include, butare not limited to, apomorphine, racemic and optically pure sibutraminemetabolites, and pharmaceutically acceptable salts, solvates, andclathrate thereof. Pharmaceutical compositions of the invention canfurther comprise other drug substances, including, but not limited to,5-HT₃ antagonists.

The invention encompasses the use of racemic and optically puresibutramine metabolites as effective dopamine, serotonin, andnorepinephrine reuptake inhibitors. Racemic and optically puresibutramine metabolites include, but are not limited to,(+)-desmethylsibutramine, (−)-desmethylsibutramine,(±)-desmethylsibutramine, (+)-didesmethylsibutramine,(−)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

4. DETAILED DESCRIPTION OF THE INVENTION

This invention relates to methods and compositions that inhibit thereuptake of neuronal monoamines (e.g., dopamine, serotonin, andnorepinephrine). The invention thereby provides a method of treating orpreventing a disorder ameliorated by the inhibition of neuronalmonoamine reuptake which comprises administering to a patient (i.e., ahuman) in need of such treatment or prevention a therapeutically orprophylactically effective amount of neuronal monoamine reuptakeinhibitor. Preferred neuronal monoamine reuptake inhibitors are racemicand optically pure sibutramine metabolites and pharmaceuticallyacceptable salts, solvates, and clathrates thereof.

As used herein, the term “treating or preventing disorders amelioratedby inhibition of neuronal monoamine reuptake” means relief from symptomsof conditions associated with abnormal neuronal monoamine levels.Disorders ameliorated by inhibition of neuronal monoamine reuptakeinclude, but are not limited to, erectile dysfunction, affectivedisorders, weight gain or obesity, cerebral function disorders, pain,obsessive-compulsive disorder, substance abuse, chronic disorders,anxiety, eating disorders, migraines, and incontinence.

A first embodiment of the invention encompasses a method of treating orpreventing erectile dysfunction which comprises adjunctivelyadministering to a patient in need of such treatment or preventiontherapeutically or prophylactically effective amounts of a dopaminereuptake inhibitor and a 5-HT₃ antagonist. Preferred dopamine reuptakeinhibitors include, but are not limited to, apomorphine, sibutramine,racemic and optically pure sibutramine metabolites, and pharmaceuticallyacceptable salts, solvates, and clathrates thereof. Particularlypreferred dopamine reuptake inhibitors are racemic and optically puresibutramine metabolites. Preferred 5-HT₃ antagonists are antiemeticagents. Examples of suitable 5-HT₃ antagonists include, but are notlimited to, granisetron (KYTRIL®), metoclopramide (REGLAN®), ondansetron(ZOFRAN®), renzapride, zacopride, tropisetron, and optically purestereoisomers, active metabolites, and pharmaceutically acceptablesalts, clathrates, and solvates thereof.

In a preferred method of this embodiment, the dopamine reuptakeinhibitor is administered transdermally or mucosally (e.g., nasally,sublingually, or buccally). In a more preferred method of thisembodiment, the dopamine reuptake inhibitor and the 5-HT₃ antagonist areboth administered transdermally or mucosally.

A second embodiment of the invention encompasses a method of treating orpreventing erectile dysfunction which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. In a preferred method of this embodiment, theracemic or optically pure sibutramine metabolite or pharmaceuticallyacceptable salt, solvate, or clathrate thereof is administeredtransdermally or mucosally.

A third embodiment of the invention encompasses a method of treating orpreventing an affective disorder which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. Affective disorders include, but are not limitedto, depression (e.g., melancholia), attention deficit disorder(including attention deficit disorder with hyperactivity and attentiondeficit/hyperactivity disorder), bipolar and manic conditions, dysthymicdisorder, and cyclothymic disorder. As used herein, the terms “attentiondeficit disorder” (ADD), “attention deficit disorder with hyperactivity”(ADDH), and “attention deficit/hyperactivity disorder” (AD/HD), are usedin accordance with their accepted meanings in the art. See, e.g.,Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed.,American Psychiatric Association, 1997 (DSM-IV™) and Diagnostic andStatistical Manual of Mental Disorders, 3^(rd) Ed., American PsychiatricAssociation (1981) (DSM-III™).

A preferred method of this embodiment is a method of treating orpreventing attention deficit disorder which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. In the treatment or prevention of attentiondeficit disorder, the racemic or optically pure sibutramine metaboliteis an optically pure sibutramine metabolite, and more preferably is(−)-desmethylsibutramine or (−)-didesmethylsibutramine.

Another preferred method of this embodiment is a method of treating orpreventing depression which comprises administering to a patient in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a racemic or optically pure sibutramine metabolite,or a pharmaceutically acceptable salt, solvate, or clathrate thereof. Asused herein, the term “treating or preventing depression” means relieffrom or prevention of the symptoms of depression which include, but arenot limited to, changes in mood, feelings of intense sadness, despair,mental slowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Physical changes can also be relieved or prevented bythis method, and include, but are not limited to, insomnia, anorexia,decreased energy and libido, and abnormal hormonal circadian rhythms.

A fourth embodiment of the invention encompasses a method of treating orpreventing weight gain or obesity which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. As used herein, the term “treating or preventingweight gain or obesity” means reduction of weight, relief from beingoverweight, relief from gaining weight, or relief from obesity, andprevention from gaining weight, all of which are usually due tounnecessary consumption of food.

A fifth embodiment of the invention encompasses a method of treating orpreventing a cerebral function disorder which comprises administering toa patient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. Cerebral function disorders include, but are notlimited to, senile dementia, Alzheimer's type dementia, memory loss,amnesia/amnestic syndrome, disturbance of consciousness, coma, loweringof attention, speech disorders, Parkinson's disease, Lennox syndrome,autism, epilepsy, hyperkinetic syndrome, and schizophrenia. Cerebralfunction disorders can be induced by factors including, but not limitedto, cerebrovascular diseases, such as cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis, andhead injuries, and conditions having symptoms selected from the groupconsisting of disturbances of consciousness, senile dementia, coma,lowering of attention, and speech disorders. As used herein, the term“treating or preventing a cerebral function disorder” means relief fromor prevention of one or more symptoms associated with cerebral functiondisorders.

A sixth embodiment of the invention encompasses a method of treating orpreventing pain, including chronic pain and neuropathic pain, whichcomprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of aracemic or optically pure sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof.

A specific embodiment of the invention is directed to a method oftreating or preventing neuropathic pain which comprises administering toa patient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. Examples of neuropathic pain which can be treatedby this method include, but are not limited to: thoracic outletobstruction syndromes; compression and entrapment neuropathies such asulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey,radial nerve palsey; and Guillain-Barré syndrome. Additional examples ofneuropathic pain which can be treated according to this method includepain associated with or resulting from: trauma caused by injury orsurgical operation; tumors; bony hyperostosis; casts; crutches;prolonged cramped postures; hemorrhage into a nerve; exposure to cold orradiation; collagen-vascular disorders; metabolic diseases such asdiabetes; infectious diseases such as Lyme disease and HIV; toxins suchas emetine, hexobarbital, barbital, chlorobutanol, sulfonamides,phenytoin, nitrofurantoin, the vinca alkaloids, heavy metals, carbonmonoxide, triorthocresylphosphate, orthodinitrophenol, and othersolvents and industrial poisons; autoimmune reactions; nutritionaldeficiency, and vitamin B deficiency in particular; and metabolicdisorders such as hypothyroidism, porphyria, sarcoidosis, amyloidosis,uremia and diabetes. In one particular embodiment of the invention, theneuropathic pain is diabetic peripheral neuropathy.

A seventh embodiment of the invention encompasses a method of treatingor preventing an obsessive-compulsive disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof.

An eighth embodiment of the invention encompasses a method of treatingor preventing substance abuse which comprises administering to a patientin need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. As used herein, the term “substance abuse”encompasses the abuse of, and physical and/or psychological addictionto, drugs or alcohol. The term “substance abuse” further encompasses itsaccepted meaning in the art. See, e.g., DSM-IV™ and DSM-III™.

A preferred method encompassed by this embodiment is a method oftreating or preventing cocaine and/or heroin abuse.

A ninth embodiment of the invention encompasses a method of treating orpreventing nicotine addiction which comprises administering to a patientin need of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. Nicotine addiction includes nicotine addiction ofall known forms, such as smoking cigarettes, cigars and/or pipes, andaddiction to chewing tobacco.

A tenth embodiment of the invention encompasses a method of elicitingsmoking cessation which comprises administering to a patient who smokestobacco a therapeutically effective amount of a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof.

In a preferred method encompassed by this embodiment, the racemic oroptically pure sibutramine metabolite or pharmaceutically acceptablesalt, solvate, or clathrate thereof is administered orally, mucosally,or transdermally. In a more preferred method, the racemic or opticallypure sibutramine metabolite or pharmaceutically acceptable salt,solvate, or clathrate thereof is administered transdermally.

Another preferred method encompassed by this embodiment is a method ofeliciting smoking cessation which comprises adjunctively administeringto a patient who smokes tobacco therapeutically effective amounts of aracemic or optically pure sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, and nicotine.Preferably, the nicotine and/or racemic or optically pure sibutraminemetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered orally, mucosally, or transdermally. Morepreferably, the nicotine and/or racemic or optically pure sibutraminemetabolite or pharmaceutically acceptable salt, solvate, or clathratethereof is administered transdermally.

Another method encompassed by this embodiment is a method of treating orpreventing weight gain associated with smoking cessation which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof.

An eleventh embodiment of the invention encompasses a method of treatingor preventing a chronic disorder selected from the group consisting ofnarcolepsy, chronic fatigue syndrome, seasonal affective disorder,fibromyalgia, and premenstrual syndrome (or premenstrual dysphoricdisorder). This method comprises administering to a patient in need ofsuch treatment or prevention a therapeutically or prophylacticallyeffective amount of a racemic or optically pure sibutramine metabolite,or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

Preferred methods of this embodiment are methods of treating orpreventing premenstrual syndrome, narcolepsy, and chronic fatigue.

A twelfth embodiment of the invention encompasses a method of treatingor preventing anxiety which comprises administering to a patient in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a racemic or optically pure sibutramine metabolite,or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

A thirteenth embodiment of the invention encompasses a method oftreating or preventing an eating disorder which comprises administeringto a patient in need of such treatment or prevention a therapeuticallyor prophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof.

A fourteenth embodiment of the invention encompasses a method oftreating or preventing a migraine or migraine headache which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof.

As used herein, the terms “obsessive-compulsive disorder,”“pre-menstrual syndrome,” “anxiety,” “eating disorder,” and “migraine”are used consistently with their accepted meanings in the art. See,e.g., DSM-IV™ and DSM-III™. The term “methods of treating or preventing”when used in connection with these disorders means the amelioration,prevention, or relief from symptoms and/or effects associated with thesedisorders.

A fifteenth embodiment of the invention encompasses a method of treatingor preventing incontinence which comprises administering to a patient inneed of such treatment or prevention a therapeutically orprophylactically effective amount of a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof. In particular, a racemic or optically puresibutramine metabolite can be used to treat fecal incontinence, stressurinary incontinence (“SUI”), urinary exertional incontinence, urgeincontinence, reflex incontinence, passive incontinence and overflowincontinence.

As used herein, the term “treating or preventing incontinence” meanstreatment, prevention of, or relief from the symptoms of incontinenceincluding involuntary voiding of feces or urine, and dribbling orleakage or feces or urine, which may be due to one or more causesincluding, but not limited to, pathology altering sphincter control,loss of cognitive function, overdistention of the bladder,hyper-reflexia and/or involuntary urethral relaxation, weakness of themuscles associated with the bladder or neurologic abnormalities.

A preferred method encompassed by this embodiment is a method oftreating or preventing stress urinary incontinence. In a furtherpreferred method encompassed by this embodiment, the patient is an elderhuman of an age greater than 50 or a child of an age less than 13.

Another embodiment of the invention encompasses optically puresibutramine metabolites such as, but not limited to,(R)-desmethylsibutramine, (S)-desmethylsibutramine,(R)-didesmethylsibutramine, and (S)-didesmethylsibutramine, andpharmaceutically acceptable salts, solvates and clathrates thereof. Inparticular, this invention encompasses the tartarate, mandelate, andhydrochloride salts of (R)-desmethylsibutramine,(S)-desmethylsibutramine, (R)-didesmethylsibutramine, and(S)-didesmethylsibutramine.

This invention further encompasses compounds of the formula:

and pharmaceutically acceptable salts, solvates and clathrates thereof,wherein R is alkyl, more preferably C₁-C₆ alkyl, even more preferablymethyl, ethyl, or propyl, and most preferably methyl.

This invention also encompasses the compound of the formula:

and pharmaceutically acceptable salts, solvates and clathrates thereof.

Another embodiment of the invention encompasses a method of preparing acompound of Formula 2:

which comprises contacting cyclobutanecarbonitrile withdiisobutylaluminum hydride to form an intermediate; and reacting theintermediate with CH₃NH₂ at a temperature and for a time sufficient toform the compound of Formula 2.

Another embodiment of the invention encompasses a method of preparingracemic or optically pure desmethylsibutramine which comprisescontacting a compound of Formula 2 with a compound of the formula AMX,wherein A is aryl, alkyl, or aralkyl, M is Li or Mg, and X is a halogenatom (e.g., Br or I).

The invention further encompasses a method of preparing optically pure(R)-desmethylsibutramine or a pharmaceutically acceptable salt, solvateor clathrate thereof which comprises contacting racemicdesmethylsibutramine with (R)-mandelic acid in a solvent which is orwhich comprises a mixture of ethyl acetate and heptane to form the(R)-mandelate salt of (R)-desmethylsibutramine.

The invention further encompasses a method of preparing optically pure(S)-desmethylsibutramine or a pharmaceutically acceptable salt, solvateor clathrate thereof which comprises contacting racemicdesmethylsibutramine with (S)-mandelic acid in a solvent which is orwhich comprises a mixture of ethyl acetate and heptane to form the(S)-mandelate salt of (S)-desmethylsibutramine.

The invention further encompasses a method of preparing optically pure(R)-didesmethylsibutramine or a pharmaceutically acceptable salt,solvate or clathrate thereof which comprises contacting racemicdidesmethylsibutramine with (R)-mandelic acid in a solvent which is orwhich comprises a mixture of acetonitrile and methanol to form the(R)-mandelate salt of (R)-didesmethylsibutramine.

The invention further encompasses a method of preparing optically pure(S)-didesmethylsibutramine or a pharmaceutically acceptable salt,solvate or clathrate thereof which comprises contacting racemicdidesmethylsibutramine with (S)-mandelic acid in a solvent which is orwhich comprises a mixture of acetonitrile and methanol to form the(S)-mandelate salt of (S)-didesmethylsibutramine.

Another embodiment of the invention encompasses pharmaceuticalcompositions and dosage forms comprising a racemic or optically puresibutramine metabolite or a pharmaceutically acceptable salt, solvate,or clathrate thereof. These pharmaceutical compositions and dosage formsare particularly useful in the methods described above. For example,dosage forms of the invention are suitable for oral, mucosal (e.g.,nasal, sublingual, buccal, rectal, and vaginal), parenteral (e.g.,intravenous and intramuscular), transdermal, or subcutaneousadministration. Preferred dosage forms of the invention are suitable fororal, mucosal, or transdermal administration.

Preferred racemic and optically pure sibutramine metabolites include,but are not limited to, (+)-desmethylsibutramine,(−)-desmethylsibutramine, (±)-desmethylsibutramine,(+)-didesmethylsibutramine, (−)-didesmethylsibutramine, and(±)-didesmethylsibutramine.

Optically pure metabolites of sibutramine are most preferred. As usedherein, the term “optically pure” means that a composition containsgreater than about 90% of the desired stereoisomer by weight, preferablygreater than about 95% of the desired stereoisomer by weight, and morepreferably greater than about 99% of the desired stereoisomer by weight,based upon the total weight of the active ingredient. For example,optically pure (+)-desmethylsibutramine is substantially free of(−)-desmethylsibutramine. As used herein, the term “substantially free”means that a composition contains less than about 10 weight percent,preferably less than about 5 weight percent, and more preferably lessthan about 1 weight percent of a compound.

It is contemplated that pharmaceutically acceptable salts, solvates, andclathrates of racemic and optically pure sibutramine metabolites be usedin the methods, pharmaceutical compositions, and dosage forms of theinvention. As used herein, the term “pharmaceutically acceptable salt”refers to a salt prepared from a pharmaceutically acceptable non-toxicinorganic or organic acid. Inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, andphosphoric. Organic acids include, but are not limited to, aliphatic,aromatic, carboxylic, and sulfonic organic acids including, but notlimited to, formic, acetic, propionic, succinic, benzoiccamphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic,mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic,furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,pantothenic, benzenesulfonic, stearic, sulfanilic, alginic, andgalacturonic acid. Particularly preferred acids are hydrobromic,hydrochloric, phosphoric, and sulfuric acids, and most particularlyreferred is hydrochloric acid.

In each of the methods of the invention, a sibutramine metabolite or apharmaceutically acceptable salt, solvate, or clathrate thereof, can beadjunctively administered with one or more additional pharmacologicallyactive compounds, i.e., the sibutramine metabolite and at least oneadditional pharmacologically active compound are administered as acombination, concurrently but separately, or sequentially by anysuitable route (e.g., orally, transdermally, or mucosally). Further,preferred pharmaceutical compositions and dosage forms of the inventioncan comprise a pharmaceutically acceptable excipient and/or at least oneadditional pharmacologically active compound.

Additional pharmacologically active compounds that can be used in themethods and compositions of the invention include, but are not limitedto, drugs that act on the central nervous system (“CNS”), such as, butnot limited to: 5-HT (e.g., 5-HT₃ and 5-HT_(1A)) agonists andantagonists; selective serotonin reuptake inhibitors (“SSRIs”);hypnotics and sedatives; drugs useful in treating psychiatric disordersincluding antipsychotic and neuroleptic drugs, antianxiety drugs,antidepressants, and mood-stabilizers; CNS stimulants such asamphetamines; dopamine receptor agonists; antimonic agents; antipanicagents; cardiovascular agents (e.g., beta blockers and angiotensinconverting enzyme inhibitors); antivirals; antibiotics; antifungals; andantineoplastics.

More specific drugs that act on the CNS include, but are not limited to,SSRIs, benzodiazepine compounds, tricyclic antidepressants,antipsychotic agents, anti-anxiolytic agents, β-adrenergic antagonists,5-HT_(1A) receptor antagonists, and 5-HT₃ receptor agonists. Even morespecific drugs that act on the CNS include, but are not limited to,lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine,and valium.

Selective serotonin reuptake inhibitors are compounds that inhibit thecentral nervous system uptake of serotonin while having reduced orlimited affinity for other neurologically active receptors. Examples ofSSRIs include, but are not limited to, citalopram (CELEXA®); fluoxetine(PROZAC®) fluvoxamine (LUVOX®); paroxetine (PAXIL®); sertraline(ZOLOFT®); venlafaxine (EFFEXOR®); and optically pure stereoisomers,active metabolites, and pharmaceutically acceptable salts, solvates, andclathrates thereof.

Benzodiazepine compounds that can be used in the methods andcompositions of the invention include, but are not limited to, thosedescribed in Goodman & Gilman, The Pharmacological Basis ofTherapeutics, 362-373 (9^(th) ed. McGraw-Hill, 1996). Examples ofspecific benzodiazepines include, but are not limited to, alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, triazolam, pharmacologically active metabolites andstereoisomers thereof, and pharmaceutically acceptable salts, solvates,clathrates thereof. The tradenames of some of these compounds areprovided below.

Alprazolam, which is chemically named8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepine, issold under the tradename XANAX®. XANAX® is indicated for the managementof anxiety disorder (a condition corresponding most closely to theDSM-III™ diagnosis of generalized anxiety disorder) or the short-termrelief of symptoms of anxiety. Physician's Desk Reference® 2516-2521(53^(rd) ed., 1999).

The hydrochloride salt of chlordiazepoxide, which is chemically named7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxidehydrochloride, is sold under the tradename LIBRIUM®. LIBRIUM® isindicated for the management of anxiety disorders or for the short-termrelief of symptoms of anxiety, withdrawal symptoms of acute alcoholism,and preoperative apprehension and anxiety. Physician's Desk Reference®1369-1370 (53^(rd) ed., 1999).

Clonazepam, which is chemically named5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one, issold under the tradename KLONOPIN®. KLONOPIN® is useful alone or as anadjunct in the treatment of the Lennox-Gastaut syndrome (petit malvariant), akinetic and myoclonic seizures. KLONOPIN® is also indicatedfor the treatment of panic disorder, with or without agoraphobia, asdefined in DSM-III™. Physician's Desk Reference® 2688-2691 (53^(rd) ed.,1999).

The dipotassium salt of clorazepate, which is chemically named7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicdipotassium, is sold under the tradename TRANXENE®. TRANXENE® isindicated for the management of anxiety disorders or for the short-termrelief of the symptoms of anxiety, as adjunctive therapy in themanagement of partial seizures, and for the symptomatic relief of acutealcohol withdrawal. Physician's Desk Reference® 475-476 (53^(rd) ed.,1999).

Diazepam, which is chemically named7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, issold under the tradename VALIUM®. VALIUM® is indicated for themanagement of anxiety disorders or for the short-term relief of thesymptoms of anxiety. Physician's Desk Reference® 2735-2736 (53^(rd) ed.,1999).

Estazolam, which is chemically named8-chloro-6-phenyl-4H-s-triazolo[4-3-α][1,4]benzodiazepine, is sold underthe tradename PROSOM™. PROSOM™ is indicated for the short-termmanagement of insomnia characterized by difficulty in falling asleep,frequent nocturnal awakenings, and/or early morning awakenings.Physician's Desk Reference® 473-475 (53^(rd) ed., 1999).

Flumazenil, which is chemically named ethyl8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α](1,4)benzodiazepine-3-carboxylate,is sold under the tradename ROMAZICON®. ROMAZICON® is indicated for thecomplete or partial reversal of the sedative effects of benzodiazepinesin cases where general anesthesia has been induced and/or maintainedwith benzodiazepines, where sedation has been produced withbenzodiazepines for diagnostic and therapeutic procedures, and for themanagement of benzodiazepine overdose. Physician's Desk Reference®2701-2704 (53^(rd) ed., 1999).

The hydrochloride salt of flurazepam, which is chemically named7-chloro-1-[2-(di-ethylamino)ethyl]-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride, is sold underthe tradename DALMANE®. DALMANE® is a hypnotic agent useful for thetreatment of insomnia characterized by difficulty in falling asleep,frequent nocturnal awakenings, and/or early morning awakenings.Physician's Desk Reference® 2520 (52^(nd) ed., 1998).

Lorazepam, which is chemically named7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one,is sold under the tradename ATIVAN®. ATIVAN® is indicated for themanagement of anxiety disorders or for the short-term relief of thesymptoms of anxiety or anxiety associated with depressive symptoms.Physician's Desk Reference® 3267-3272 (53^(rd) ed., 1999).

The hydrochloride salt of midazolam, which is chemically named8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-α][1,4]benzodiazepinehydrochloride, is sold under the tradename VERSED®. VERSED® is indicatedfor preoperative sedation/anxiolysis/amnesia and general anesthesia.Physician's Desk Reference® 2720-2726 (53^(rd) ed., 1999).

Oxazepam, which is chemically named7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, issold under the tradename SERAX®.SERAX® is indicated for the managementof anxiety disorders or for the short-term relief of the symptoms ofanxiety. Physician's Desk Reference® 3383-3384 (53^(rd) ed., 1999).

Quazepam, which is chemically named7-chloro-5-(o-fluoro-phenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)2H-1,4-benzodiazepine-2-thione,is sold under the tradename DORAL®. DORAL® is indicated for thetreatment of insomnia characterized by difficulty in falling asleep,frequent nocturnal awakenings, and/or early morning awakenings.Physician's Desk Reference® 2958 (52^(nd) ed., 1998).

Temazepam, which is chemically named7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,is sold under the tradename RESTORIL®. RESTORIL® is indicated for theshort-term treatment of insomnia. Physician's Desk Reference® 2075-2078(53^(rd) ed., 1999).

Triazolam, which is chemically named8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-tria-zolo-[4,3-α][1,4]benzodiazepine, is sold under the tradename HALCION®. HALCION® isindicated for the short-term treatment of insomnia. Physician's DeskReference® 2490-2493 (53^(rd) ed., 1999).

The clinician, physician, or psychiatrist will appreciate which of theabove compounds can be used in combination with a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, for the treatment or prevention of agiven disorder, although preferred combinations are disclosed herein.

Disorders that can be treated or prevented using a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, in combination with a benzodiazepine suchas those listed above include, but are not limited to, affectivedisorders (e.g., depression), anxiety, eating disorders, and cerebralfunction disorders such as those described herein.

The invention further encompasses methods of using and pharmaceuticalcompositions comprising a racemic or optically pure sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, or clathratethereof, in combination with an antipsychotic agent. Antipsychoticagents are used primarily in the management of patients with psychoticor other serious psychiatric illness marked by agitation and impairedreasoning. These drugs have other properties that possibly are usefulclinically, including antiemetic and antihistamine effects and theability to potentiate analgesics, sedatives, and general anesthetics.Specific antipsychotic drugs are tricyclic antipsychotic drugs, of whichthere are three subtypes: phenothiazines, thioxanthenes, and otherheterocyclic compounds, all of which can be used in the methods andcompositions of the invention. See, e.g., Goodman & Gilman, ThePharmacological Basis of Therapeutics, 404 (9^(th) ed. McGraw-Hill,1996).

Specific tricyclic antipsychotic compounds include, but are not limitedto, chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprothixene,thiothixene, clozapine, haloperidol, loxapine, molindone, pimozide,risperidone, desipramine, pharmacologically active metabolites andstereoisomers thereof, and pharmaceutically acceptable salts, solvates,clathrates thereof. The tradenames of some of these compounds areprovided herein.

Chlorpromazine, which is chemically named10-(3-dimethylaminopropyl)-2-chlorphenothiazine, is sold under thetradename THORAZINE®. THORAZINE® is indicated, inter alia, for themanagement of manifestations of psychotic disorders. Physician's DeskReference® 3101-3104 (53^(rd) ed., 1999).

The besylate salt of mesoridazine, which is chemically named10-[2(1-methyl-2-piperidyl)ethyl]-2-methyl-sylfinyl)-phenothiazine, issold under the tradename SERENTIL®. SERENTIL® is indicated in thetreatment of schizophrenia, behavioral problems in mental deficiency andchronic brain syndrome, alcoholism, and psychoneurotic manifestations.Physician's Desk Reference® 764-766 (53^(rd) ed., 1999).

Perphenazine, which is chemically named4-[3-(2-chlorophenothiazin-10-yl)propyl-1-piperazineethanol, is soldunder the tradename TRILAFON®. TRILAFON® is indicated for use in themanagement of the manifestations of psychotic disorders and for thecontrol of severe nausea and vomiting in adults. Physician's DeskReference® 2886-2888 (53^(rd) ed., 1999).

Trifluoperazine, which is chemically named10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-10H-phenothiazine,is sold under the tradename STELAZINE®. STELAZINE® is indicated for themanagement of the manifestations of psychotic disorders and for theshort-term treatment of generalized non-psychotic anxiety. Physician'sDesk Reference® 3092-3094 (53^(rd) ed., 1999).

Thiothixene, which is chemically namedN,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthene-2-sulfonamide,is sold under the tradename NAVANE®. NAVANE® is indicated in themanagement of manifestations of psychotic disorders. Physician's DeskReference® 2396-2399 (53^(rd) ed., 1999).

Clozapine, which is chemically named8-chloro-11-(4-methyl-1-piperazinyl)5H-dibenzo[b,e][1,4]diazepine, issold under the tradename CLOZARIL®. CLOZARIL® is indicated for themanagement of severely ill schizophrenic patients who fail to respondadequately to standard antipsychotic drug treatment. Physician's DeskReference® 2004-2009 (53^(rd) ed., 1999).

Haloperidol, which is chemically named4-[4-(p-chlorophenyl)-4-hydroxy-piperidonol-4′-fluorobutyrophenone, issold under the tradename HALDOL®. HALDOL® is indicated for use in themanagement of patients requiring prolonged parenteral antipsychotictherapy (e.g., patients with chronic schizophrenia). Physician's DeskReference® 2190-2192 (53^(rd) ed., 1999).

Loxapine, which is chemically named2-chloro-11-(4-methyl-1-piperazinyl)dibenz[bf][1-4]oxaxepine, is soldunder the tradename LOXITANE®. LOXITANE® is indicated for the managementof the manifestations of psychotic disorders. Physician's DeskReference® 3224-3225 (53^(rd) ed., 1999).

Molindone, which is chemically named3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl) indol-4(5H)-onehydrochloride, is sold under the tradename MOBAN®. MOBAN® is indicatedfor the management of the manifestations of psychotic disorders.Physician's Desk Reference® 978-979 (53^(rd) ed., 1999).

Pimozide, which is chemically named,1-[1-[4,4-bis(4-fluorophenyl)butyl]4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one,is sold under the tradename ORAP®. ORAP® is indicated for thesuppression of motor and phonic tics in patients with Tourette'sDisorder who have failed to respond satisfactorily to standardtreatment. Physician's Desk Reference® 1054-1056 (53^(rd) ed., 1999).

Risperidone, chemically named3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,is sold under the tradename RISPERDAL®. RISPERDAL® is indicated for themanagement of the manifestations of psychotic disorders. Physician'sDesk Reference® 1432-1436 (53^(rd) ed., 1999).

The hydrochloride salt of desipramine, which is chemically named5H-Dibenz[bf]azepine-5-propanamine-10,11-dihydro-N-methyl-monohydrochloride,is sold under the tradename NORPRAMIN®. NORPRAMIN® is indicated for thetreatment of depression. Physician's Desk Reference® 1332-1334 (53^(rd)ed., 1999).

Disorders that can be treated or prevented using a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, in combination with an antipsychoticcompound, and particularly a tricyclic antipsychotic compound, include,but are not limited to, affective disorders (e.g., depression), anxiety,eating disorders, and cerebral function disorders (e.g., schizophrenia)such as those described herein.

The invention further encompasses methods of using and pharmaceuticalcompositions comprising a racemic or optically pure sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, or clathratethereof, in combination with a 5-HT_(1A) receptor antagonist and/or a13-adrenergic antagonist. Examples of 5-HT_(1A) receptor antagonists andβ-adrenergic antagonists that can be used in the methods andcompositions of the invention include, but are limited to: alprenolol;WAY 100135; spiperone; pindolol; (S)-UH-301; penbutolol; propranolol;tertatolol; a compound of the formula I as disclosed in U.S. Pat. No.5,552,429, which is incorporated herein by reference; pharmacologicallyactive metabolites and stereoisomers thereof; and pharmaceuticallyacceptable salts, solvates, clathrates thereof.

Alprenolol, which is chemically named1-(1-methylethyl)amino-3-[2-(2-propenyl)phenoxy]-2-propanol, isdescribed by U.S. Pat. No. 3,466,325, which is incorporated herein byreference.

WAY 100135, which is chemically namedN-(t-butyl)-3-[4-(2-methoxphenyl)-piperazin-1-yl]-2-phenylpropanamide,is described by U.S. Pat. No. 4,988,814, which is incorporated herein byreference. See also, Cliffe et al., J. Med. Chem., 36:1509-1510 (1993).

Spiperone, which is chemically named8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one),is described by U.S. Pat. Nos. 3,155,669 and 3,155,670, both of whichare incorporated herein by reference. See also, Middlmiss et al.,Neurosci. and Biobehav. Rev., 16:75-82 (1992).

Pindolol, which is chemically named4-(2-hydroxy-3-isopropylaminopropoxy)-indole, is described by U.S. Pat.No. 3,471,515, which is incorporated herein by reference. See also,Dreshfield et al., Neurochem. Res., 21(5):557-562 (1996).

(S)-UH-301, which is chemically named(S)-5-fluoro-8-hydroxy-2-dipropylamino-tetralin), is well known topharmacologists and pharmaceutical chemists. See, e.g., Hillyer et al.,J. Med. Chem., 33:1541-44 (1990) and Moreau et al., Brain Res. Bull.,29:901-04 (1992).

Penbutolol, which is chemically named(1-(t-butylamino)-2-hydroxy-3-(2-cyclopentyl-phenoxy)propane), is soldunder the tradename LEVATOL®. LEVATOL® is indicated the treatment ofmild to moderate arterial hypertension. Physician's Desk Reference®2908-2910 (53^(rd) ed., 1999).

The hydrochloride salt of propranolol, which is chemically named1-isopropylamino-3-(1-naphthalenyloxy)-2-propanol hydrochloride, is soldunder the tradename INDERAL®. INDERAL® is indicated in the management ofhypertension. Physician's Desk Reference® 3307-3309 (53^(rd) ed., 1999).

Tertatolol, chemically named8-(3-t-butylamino-2-hydroxypropyloxy)-thiochroman, is described by U.S.Pat. No. 3,960,891, which is incorporated herein by reference.

Disorders that can be treated or prevented using a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, in combination with a 5-HT_(1A) receptorantagonist include, but are not limited to, depression,obsessive-compulsive disorders, eating disorders, hypertension,migraine, essential tremor, hypertrophic subaortic stenosis andpheochromocytoma. A specific disorder that can be treated or preventedis posttraumatic depression disorder.

Disorders that can be treated or prevented using a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, in combination with a β-adrenergicantagonist include, but are not limited to, post myocardial infarctiondepression. Specific β-adrenergic antagonists include, but are notlimited to, S(−)-pindolol, penbutolol, and propranolol.

The invention further encompasses methods of using and pharmaceuticalcompositions comprising a racemic or optically pure sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, or clathratethereof, in combination with a non-benzodiazepine or non-tricyclicagents. Examples of such additional pharmacologically active compoundsinclude, but are limited to: olanzapine, buspirone, hydroxyzine,tomoxetine, pharmacologically active metabolites and stereoisomersthereof, and pharmaceutically acceptable salts, solvates, clathratesthereof.

Olanzapine, which is chemically named2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,is sold under the tradename ZYPREXA®. ZYPREXA® is indicated for themanagement of the manifestations of psychotic disorders. Physician'sDesk Reference® 1641-1645 (53^(rd) ed., 1999).

The hydrochloride salt of buspirone, which is chemically named8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro-[4.5]decane-7,9-dionemonohydrochloride, is sold under the tradename BUSPAR®. BUSPAR® isindicated for the management of anxiety disorders or the short-termrelief of the symptoms of anxiety. Physician's Desk Reference® 823-825(53^(rd) ed., 1999).

The hydrochloride salt of hydroxyzine, which is chemically named1-(p-chlorobenzhydryl)-4[2-(2-hydroxyethoxy)-ethyl] piperazinedihydrochloride, is sold under the tradename ATARAX®. ATARAX® isindicated for symptomatic relief of anxiety and tension associated withpsychoneurosis and as an adjunct in organic disease states in whichanxiety is manifested. Physician's Desk Reference® 2367-2368 (53^(rd)ed., 1999).

Disorders that can be treated or prevented using a racemic or opticallypure sibutramine metabolite, or a pharmaceutically acceptable salt,solvate, or clathrate thereof, in combination with a compound selectedfrom the group consisting of lorazepam, tomoxetine, olanzapine,respiradone, buspirone, hydroxyzine, valium, pharmacologically activemetabolites and stereoisomers thereof, and pharmaceutically acceptablesalts, solvates, clathrates thereof include, but are not limited to,anxiety, depression, hypertension, and attention deficit disorders.

While all combinations of racemic and optically pure sibutraminemetabolites and pharmaceutically acceptable salts, solvates, andclathrate thereof, and one or more above described pharmacologicallyactive compounds can be useful and valuable, certain combinations areparticularly preferred. Examples of preferred combinations include thosewherein a racemic or optically pure sibutramine metabolite, or apharmaceutically acceptable salt, solvate, or clathrate thereof, iscombined with one of the following:

alprazolam; estazolam; oxazepam; brotizolam; flumazenil; prazepam;chlordiazepoxide; flurazepam; quazepam; clobazam; halazepam; temazepam;clonazepam; lorazepam; triazolam; clorazepate; midazolam;chlorpromazine; demoxepam; nitrazepam; mesoridazine; diazepam;nordazepam; thioridazine; acetophenazine; pimozide; propranolol;fluphenazine; risperidone; tertatolol; perphenazine; alprenolol;desipramine; trifluoperazine; WAY 100135; clonidine; chlorprothixene;spiperone; olanzapine; thiothixene; S(−)-pindolol; methylphenidate;clozapine; R(+)-pindolol; buspirone; haloperidol; racemic pindolol;hydroxyzine; and loxapine; (S)-UH-301; tomoxetine. molindone;penbutolol;

4.1 SYNTHESIS OF SIBUTRAMINE METABOLITES

Racemic sibutramine, desmethylsibutramine, and didesmethylsibutraminecan be prepared by methods known to those of ordinary skill in the art.See, e.g., U.S. Pat. No. 4,806,570, which is incorporated herein byreference; J. Med. Chem., 2540 (1993) (tosylation and azidereplacement); Butler, D., J. Org. Chem., 36:1308 (1971) (cycloalkylationin DMSO); Tetrahedron Lett., 155-58 (1980) (Grignard addition to nitrilein benzene); Tetrahedron Lett., 857 (1997) (OH to azide); and Jeffery,J. E., et al., J. Chem. Soc. Perkin. Trans 1, 2583 (1996). Opticallypure enantiomers of sibutramine and its metabolites can also be preparedusing techniques known in the art. A preferred technique is resolutionby fractional crystallization of diastereomeric salts formed withoptically active resolving agents. See, e.g., “Enantiomers, Racematesand Resolutions,” by J. Jacques, A. Collet, and S. H. Wilen,(Wiley-Interscience, N.Y., 1981); S. H. Wilen, A. Collet, and J.Jacques, Tetrahedron, 2725 (1977); E. L. Eliel Stereochemistry of CarbonCompounds (McGraw-Hill, N.Y., 1962); and S. H. Wilen Tables of ResolvingAgents and Optical Resolutions 268 (E. L. Eliel ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972).

Because sibutramine, desmethylsibutramine, and didesmethylsibutramineare basic amines, diastereomeric salts of these compounds that aresuitable for separation by fractional crystallization are readily formedby addition of optically pure chiral acid resolving agents. Suitableresolving agents include, but are not limited to, optically puretartaric, camphorsulfonic acid, mandelic acid, and derivatives thereof.Optically pure isomers of sibutramine, desmethylsibutramine, anddidesmethylsibutramine can be recovered either from the crystallizeddiastereomer or from the mother liquor, depending on the solubilityproperties of the particular acid resolving agent employed and theparticular acid enantiomer used. The identity and optical purity of theparticular sibutramine or sibutramine metabolite isomer so recovered canbe determined by polarimetry or other analytical methods.

4.1.1. Preparation of Racemic and Optically Pure Sibutramine and SaltsThereof

Racemic and optically pure sibutramine can be prepared by methylation ofracemic (R/S) or optically pure (R or S) desmethylsibutramine (DMS) ordimethylation of didesmethylsibutramine (DDMS) under suitable reactionconditions. An example of this method is shown in Scheme 1.

According to this method, racemic or optically pure DMS or DDMS iscontacted with methylating agent at a sufficient temperature and for asufficient time to form racemic or optically pure sibutramine, afterwhich time the solvent is removed by conventional means and the productis purified by, for example, crystallization or chromatography. Examplesof suitable methylating agents include, but are not limited to, CH₃X,wherein X is halogen (e.g., I and Br), and the mixture CH₂O/HCOOH. Theprogress of the reaction can be following using any method known in theart including, for example, thin layer chromatography (TLC) and nuclearmagnetic resonance spectroscopy (NMR).

4.1.2. Preparation of Racemic and Optically Pure Desmethylsibutramineand Salts Thereof

Racemic desmethylsibutramine can be prepared as shown in Scheme 2:

According to this method, cyclobutanecarbonitrile (CCBC) is reacted witha suitable reducing agent to form a compound of Formula 1. Suitablereducing agents include, but are not limited to, these used in theStephen and Sonn-Müller reactions (e.g., HCl followed by SnCl₄ or PCl₅;see J. March, Advanced Organic Chemistry, 919 (4^(th) ed: 1992), whichis incorporated herein by reference), LiAlH₄, LiAlH(OEt)₃, NaAlH₄, anddiisobutylaluminum hydride (DIBAL). Formula 1 is then reacted with anamine to provide a compound of the formula:

wherein R is alkyl (e.g., C₁-C₆ alkyl, and in particular, methyl, ethyl,or propyl). In the particular method shown in Scheme 2, the compound ofFormula 1 is reacted with CH₃NH₂ to provide a compound of Formula 2.This reaction is preferably acid catalyzed (e.g., with HCl in water).Formula 2 is then contacted with a metal salt of the isobutyl cation toprovide desmethylsibutramine. Examples of metal salts include, but arenot limited to, compounds of the formula i-BuMX, wherein X is Br or Iand M is selected from the group consisting of Li, Mg, Zn, Cr, and Mn.See J. March, Advanced Organic Chemistry, 934-5 (4^(th) ed: 1992), whichis incorporated herein by reference. Preferably, the compound is of theformula i-BuMgBr. This reaction can be done in a solvent such as, butnot limited to, THF. Preferably, the compound of Formula 2 is contactedwith a Lewis acid prior to its reaction with the metal salt. PreferredLewis acids are selected from the group consisting of BH₃.THF, BF₃.THF,BF₃.OEt, La(O-i-Pr)₃, Zr(O-i-Pr)₄, Ti(O-i-Pr)₂Cl₂, SnCl₄, andMgBr₂.OEt₂. A particular preferred Lewis acid is BF₃.OEt.

The enantiomers of desmethylsibutramine can be resolved by the formationof chiral salts as described herein. Specific preferred chiral acidsused to form the chiral salts include, but are not limited to, tartaricand mandelic acids. If tartaric acid is used, preferred solvent systemsinclude, but are not limited to, ethanol/water and isopropylalcohol/water. If mandelic acid is used, a preferred solvent system isethyl acetate/hexane.

A method of preparing the hydrochloride salt of racemicdesmethylsibutramine ((R/S)-DMS.HCl) is shown in Scheme 3:

According to this method, CCBC is contacted with a metal salt of theisobutyl cation (e.g., a Grignard reagent) to form an adduct of Formula3, which is subsequently reduced to form racemic DDMS. Racemic DDMS isthen converted to a compound of Formula 4 by, for example, contacting itwith formic acid at a suitable temperature and for a suitable time. Thecompound of Formula 4 is contacted with a reductant such as, but notlimited to, BH₃.THF, BF₃.THF, BF₃.OEt, and LiAlH₄, and finally andconverted to the HCl salt of DMS with the addition of HCl in a suitablesolvent such as, but not limited to, t-butyl methyl ether (MTBE).

Optically pure enantiomers of desmethylsibutramine and pharmaceuticallyacceptable salts, solvate and clathrates are also readily prepared bymethods of this invention. For example, the hydrochloride salt of(R)-desmethylsibutramine ((R)-DMS.HCl) can be prepared as shown inScheme 4:

According to this method, racemic desmethylsibutramine is contacted witha resolving agent such as, but not limited to, (R)-mandelic acid toprovide the corresponding salt. A preferred solvent is EtOAc/heptane.The adduct shown in Scheme 4 is the (R)-DMS.(R)-mandelate salt, which isisolated from the mother liquor and subsequently converted to the HClsalt by conventional means, but preferably by dissolving it inEtOAc/heptane followed by base-catalyzed cleavage of the salt andreaction with HCl/MTBE.

The hydrochloride salt of (S)-desmethylsibutramine ((S)-DMS.HCl) can beprepared in an analogous manner, as shown in Scheme 5:

Racemic and optically pure desmethylsibutramine can also be prepared bymethylation of didesmethylsibutramine tartarate as shown in Scheme 6.

According to this method, HCOOH is reacted with DDMS usingbase-catalysis to provide a reaction product which is subsequentlyreduced using a reductant as, but not limited to, BH₃.THF.

4.1.3. Preparation of Racemic and Optically Pure Didesmethylsibutramineand Salts Thereof

Racemic and optically pure enantiomers of didesmethylsibutramine (DDMS)and pharmaceutically acceptable salts, solvates and clathrates thereofare also readily prepared by methods of this invention. For example, thefree base of racemic didesmethylsibutramine ((R/S)-DDMS) can be preparedas shown in Scheme 7.

According to this method, a compound such as that of Formula 3 is formedby reacting CCBC with a metal salt of the isobutyl cation such as, butnot limited to, compounds of a formula i-BuMX, wherein X is Br or I andM is selected from the group consisting of Li, Mg, Zn, Cr, and Mn.Preferably, the compound is of the formula i-BuMgBr. This adduct issubsequently reduced to provide (R/S)-DDMS. Suitable

Salts of racemic and optically pure enantiomers of DDMS are readilyformed. For example, the (D)-tartrate salt of racemicdidesmethylsibutramine ((R/S)-DDMS.(D)-TA) can be prepared as shownbelow in Scheme 8. It should be noted that the (L)-tartrate salt ofracemic didesmethylsibutramine ((R/S)-DDMS.(L)-TA) can be prepared in ananalogous manner.

Although any suitable solvent known to those skilled in the art can beused in this method, a preferred solvent is toluene.

The enantiomers of didesmethylsibutramine can be resolved by theformation of chiral salts, as described above. Preferred chiral acidsused to form the chiral salts include, but are not limited to, tartaricacid. Preferred solvent systems include, but are not limited to,acetonitrile/water/methanol and acetonitrile/methanol.

The (D)-tartrate salt of optically pure (R)-didesmethylsibutramine((R)-DDMS.(D)-TA) can be obtained from racemic didesmethylsibutraminefree base as shown in Scheme 9:

According to this method, racemic DDMS is contacted with (D)-tartaricacid in a suitable solvent. A preferred solvent is a mixture of acetone,water and methanol. The resulting tartarate salt is then isolated fromthe mother liquor and recrystalized preferably from a mixture of acetoneand water to provide (R)-DDMS.(D)-tartarate in high enantiomeric purity.

Alternatively, optically pure ((R)-DDMS.(D)-TA) can be isolated from thetartarate salt of racemic didesmethylsibutramine as shown in Scheme 10.

A method of isolating the (L)-tartrate salt of(S)-didesmethylsibutramine ((S)-DDMS.(L)-TA) from racemicdidesmethylsibutramine free base is shown in Scheme 11:

According to this method, racemic DDMS is contacted with (L)-tartaricacid in a suitable solvent. A preferred solvent is a mixture of acetone,water and methanol. The resulting tartarate salt is then isolated fromthe mother liquor and recrystalized preferably from a mixture of acetoneand water to provide (S)-DDMS.(L)-tartarate in high enantiomeric purity.

With regard to the resolution of didesmethylsibutramine, it has beenfound that if tartaric acid is used as a resolving agent, a preferredsolvent used during the resolution step is a mixture of acetonitrile,water and methanol ethanol. If mandelic acid is used as a resolvingagent, a preferred solvent is a mixture of acetonitrile and methanol.

4.2. PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

The magnitude of a prophylactic or therapeutic dose of an activeingredient in the acute or chronic management of a disorder or conditionwill vary with the severity of the disorder or condition to be treatedand the route of administration. The dose, and perhaps the dosefrequency, will also vary according to age, body weight, response, andthe past medical history of the patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors.

Suitable daily doses for the treatment or prevention of a disorderdescribed herein can be readily determined by those skilled in the art.A recommended dose of racemic or optically pure sibutramine metaboliteis from about 0.1 mg to about 60 mg per day, given as a singleonce-a-day dose in the morning or as divided doses throughout the day.Preferably, a daily dose is from about 2 mg to about 30 mg per day, morepreferably from about 5 mg to about 15 mg per day.

Suitable daily dosage ranges of additional pharmacologically activecompounds that can be adjunctively administered with a racemic oroptically pure sibutramine metabolite can be readily determined by thoseskilled in the art following dosages reported in the literature andrecommended in the Physician's Desk Reference® (53^(rd) ed., 1999).

For example, suitable daily dosage ranges of 5-HT₃ antagonists can bereadily determined by those skilled in the art and will vary dependingon factors such as those described above and the particular 5-HT₃antagonists used. In general, the total daily dose of a 5-HT₃ antagonistfor the treatment or prevention of a disorder described herein is fromabout 0.5 mg to about 500 mg, preferably from about 1 mg to about 350mg, and more preferably from about 2 mg to about 250 mg per day.

The therapeutic or prophylactic administration of an active ingredientof the invention is preferably initiated at a lower dose, e.g., fromabout 2 mg to about 8 mg of sibutramine metabolite and optionally fromabout 15 mg to about 60 mg of 5-HT₃ antagonist, and increased, ifnecessary, up to the recommended daily dose as either a single dose oras divided doses, depending on the global response of the patient. It isfurther recommended that patients aged over 65 years should receivedoses of sibutramine metabolite in the range of from about 5 mg to about30 mg per day depending on global response. It may be necessary to usedosages outside these ranges, which will be readily determinable by oneof ordinary skill in the pharmaceutical art.

The dosage amounts and frequencies provided above are encompassed by theterms “therapeutically effective,” “prophylactically effective,” and“therapeutically or prophylactically effective” as used herein. Whenused in connection with an amount of a racemic or optically puresibutramine metabolite, these terms further encompass an amount ofracemic or optically pure sibutramine metabolite that induces fewer orless sever adverse effects than are associated with the administrationof racemic sibutramine. Adverse effects associated with racemicsibutramine include, but are not limited to, significant increases insupine and standing heart rate, including tachycardia, increased bloodpressure (hypertension), increased psychomotor activity, dry mouth,dental caries, constipation, hypohidrosis, blurred or blurry vision,tension, mydriasis, seizures, formation of gallstones, renal/hepaticdysfunction, fevers, arthritis, agitation, leg cramps, hypertonia,abnormal thinking, bronchitis, dyspnea, pruritus, amblyopia, menstrualdisorder, ecchymosis/bleeding disorders, interstitial nephritis, andnervousness. See, e.g., Physician's Desk Reference® 1494-1498 (53^(rd)ed., 1999).

Adjunctively administering of two or more active ingredients inaccordance with the methods of the invention can be concurrent,sequential, or both. For example, a dopamine reuptake inhibitor and a5-HT₃ antagonist can be administered as a combination, concurrently butseparately, or by sequential administration.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Preferred routesof administration include oral, transdermal, and mucosal. As mentionedabove, administration of an active ingredient for the treatment orprevention of erectile dysfunction is preferably mucosal or transdermal.Suitable dosage forms for such routes include, but are not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

A preferred transdermal dosage form is a “reservoir type” or “matrixtype” patch, which is applied to the skin and worn for a specific periodof time to permit the penetration of a desired amount of activeingredient. For example, if an active ingredient is a sibutraminemetabolite, a preferred patch is worn for 24 hours and provides a totaldaily dose of from about 0.1 mg to about 60 mg per day. Preferably, adaily dose is from about 2 mg to about 30 mg per day, more preferably,from about 5 mg to about 15 mg per day. The patch can be replaced with afresh patch when necessary to provide constant administration of theactive ingredient to the patient.

Other dosage forms of the invention include, but are not limited to,tablets, caplets, troches, lozenges, dispersions, suspensions,suppositories, ointments, cataplasms (poultices), pastes, powders,dressings, creams, plasters, solutions, capsules, soft elastic gelatincapsules, and patches.

In one embodiment, pharmaceutical compositions and dosage forms of theinvention comprise a dopamine reuptake inhibitor, such as a racemic oroptically pure sibutramine metabolite or a pharmaceutically acceptablesalt, solvate, or clathrate thereof, and optionally an additionalpharmacologically active compound, such as a 5-HT₃ antagonist. Preferredracemic or optically pure sibutramine metabolites are(+)-desmethylsibutramine, (−)-desmethylsibutramine,(±)-desmethylsibutramine, (+)-didesmethylsibutramine,(−)-didesmethylsibutramine, and (±)-didesmethylsibutramine. Thepharmaceutical compositions and dosage forms can contain apharmaceutically acceptable carrier and optionally other therapeuticingredients known to those skilled in the art.

In practical use, an active ingredient can be combined in an intimateadmixture with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier can take a widevariety of forms depending on the form of preparation desired foradministration. In preparing the compositions for an oral dosage form,any of the usual pharmaceutical media can be employed as carriers, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, preferablywithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oral preparationsbeing preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidpharmaceutical carriers are employed. If desired, tablets can be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, an activeingredient can also be administered by controlled release means ordelivery devices that are well known to those of ordinary skill in theart, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, thedisclosures of which are incorporated herein by reference. These dosageforms can be used to provide slow or controlled-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, or microspheres or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the pharmaceutical compositions of theinvention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effect,and gradually and continually release of other amounts of drug tomaintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousinducers, including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

Pharmaceutical compositions of the invention suitable for oraladministration can be presented as discrete dosage forms, such ascapsules, cachets, or tablets, or aerosol sprays each containing apredetermined amount of an active ingredient as a powder or in granules,a solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosageforms can be prepared by any of the methods of pharmacy, but all methodsinclude the step of bringing the active ingredient into association withthe carrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation.

For example, a tablet can be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

This invention further encompasses lactose-free pharmaceuticalcompositions and dosage forms. Lactose is used as an excipient insibutramine formulations. See, e.g., Physician's Desk Reference® 1494(53^(rd) ed., 1999). Unlike the parent drug, however,desmethylsibutramine and didesmethylsibutramine are secondary andprimary amines, respectively, and so can potentially decompose over timewhen exposed to lactose. Thus, compositions of the invention thatcomprise sibutramine metabolites preferably contain little, if any,lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions of the invention can comprise excipients whichare well known in the art and are listed in the USP (XXI)/NF (XVI),which is incorporated herein by reference. In general, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate decomposition. Thus the effect of water on aformulation can be of great significance since moisture and/or humidityare commonly encountered during manufacture, handling, packaging,storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms of racemic or optically pure sibutramine metabolitewhich contain lactose are preferably anhydrous if substantial contactwith moisture and/or humidity during manufacturing, packaging, and/orstorage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

In this regard, the invention encompasses a method of preparing a solidpharmaceutical formulation comprising an active ingredient which methodcomprises admixing under anhydrous or low moisture/humidity conditionsthe active ingredient and an excipient (e.g., lactose), wherein theingredients are substantially free of water. The method can furthercomprise packaging the anhydrous or non-hygroscopic solid formulationunder low moisture conditions. By using such conditions, the risk ofcontact with water is reduced and the degradation of the activeingredient can be prevented or substantially reduced.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, for example, thematerials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, andAVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa., U.S.A.). An exemplary suitablebinder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof Thebinder/filler in pharmaceutical compositions of the present invention istypically present in about 50 to about 99 weight percent of thepharmaceutical composition.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment. Toomuch of a disintegrant will produce tablets which may disintegrate inthe bottle. Too little may be insufficient for disintegration to occurand may thus alter the rate and extent of release of the activeingredient(s) from the dosage form. Thus, a sufficient amount ofdisintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) should be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used varies based upon the type of formulation and mode ofadministration, and is readily discernible to those of ordinary skill inthe art. Typically, about 0.5 to about 15 weight percent ofdisintegrant, preferably about 1 to about 5 weight percent ofdisintegrant, can be used in the pharmaceutical composition.

Disintegrants that can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums ormixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), or mixtures thereof. A lubricant canoptionally be added, typically in an amount of less than about 1 weightpercent of the pharmaceutical composition.

Dosage forms of the invention that comprise a sibutramine metabolitepreferably contain from about 0.1 mg to about 60 mg of the metabolite orpharmaceutically acceptable salt, solvate, or clathrate thereof. Forexample, each tablet, cachet, or capsule contains from about 0.1 mg toabout 60 mg of the active ingredient. Most preferably, the tablet,cachet, or capsule contains either one of three dosages, e.g., about 10mg, about 20 mg, or about 30 mg of racemic or optically pure sibutraminemetabolites (as scored lactose-free tablets, the preferable dose form).

The invention is further defined by reference to the following examples.It will be apparent to those skilled in the art that many modifications,both to materials and methods, can be practiced without departing fromthe scope of this invention.

5. EXAMPLES

Example 1 describes the preparation of racemic and optically puresibutramine.

Examples 2-6 describe the preparation of racemic and optically pureforms of desmethylsibutramine (DMS). In each of these examples, theenantiomeric purity of DMS was determined using a Chirobiotic Vanalytical column (10 μm, 4.6 mm×25 mm) with 20 mM ammonium acetate/IPA(65:35) as the mobile phase. The UV detector was set to a wavelength of222 nm.

Examples 7-10 describe the preparation of racemic and optically pureforms of didesmethylsibutramine (DDMS). In each of these examples, theenantiomeric purity of DDMS was determined using an ULTRON ES-OVManalytical column (150 mm×4.6 mm) with 0.01 M KH₂PO₄/MeOH (70:30) as themobile phase. The UV detector was set to a wavelength of 200 nm.

Examples 11-12 describe methods of determining binding affinities of thecompounds of the invention and binding affinities measured using thosemethods.

Finally, Example 13 describes oral formulations comprising compounds ofthe invention.

5.1. Example 1

SYNTHESIS OF SIBUTRAMINE

Synthesis of 1-(4-Chlorophenyl)cyclobutanecarbonitrile

To a suspension of NaH (17.6 g 60%, washed with hexane) indimethylsulfoxide (150 mL) at room temperature with mechanical stirringwas added over a one hour period a mixture of chlorbenzylnitrile (30.3g) and 1,3-dibromopropane (22.3 mL, 44.5 g). The reaction mixture wasstirred for an additional 1 hour, and isopropyl alcohol (10 mL) wasadded slowly to quench excess NaH. Water (150 mL) was added. Thereaction mixture was extracted with t-butyl methyl ether (MTBE) (2×200mL), and the combined extracts were washed with water (3×200 mL), brine,and dried over MgSO₄. The solvent was removed in a rotoevaporator, andthe final product was purified by distillation to give the titlecompound (22 g, 56%) as pale yellow oil, bp 110-120° C./1.0 mm Hg. Theproduct was characterized by ¹H NMR.

Synthesis of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine

A solution of isobutylmagnesium bromide (2M, 108 mL) in diethyl ether(Aldrich) was concentrated to remove most of the ether. The residue wasdissolved in toluene (150 mL), followed by addition of the nitrile madeabove (22 g). The reaction mixture was heated to 105° C. for 17 hours.The reaction mixture was cooled to room temperature, and added to aslurry of NaBH₄ in isopropyl alcohol (450 mL). The reaction mixture washeated under reflux for 6 hours, cooled to room temperature andconcentrated. The residue was diluted with water (350 mL), and extractedwith ethyl acetate (3×200 mL). The combined extracts were washed withwater (100 mL), and dried (MgSO₄), and concentrated to give 24.2 g crudeproduct (83%).

Synthesis of Sibutramine Free Base

1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (21.6 g) was addedto formic acid (27 mL) and aqueous formaldehyde (46 mL). The reactionmixture was heated to 85-95° C. for 18 hours and was cooled to roomtemperature. 30% NaOH was added until the mixture was basic (pH>11). Thesolution was extracted with chloroform (3×200 mL) and the extracts werecombined and washed with water and brine and concentrated to give 15 gproduct.

Sibutramine HCl

Sibutramine free base (2.25 g) was dissolved in MTBE (20 mL) and thatsolution was added to 20 mL 1M HCl in diethyl ether. The reactionmixture was stirred for 30 minutes, and the solid was collected byfiltration to give 1.73 g after drying. The product was characterized by¹H NMR.

Resolution of Sibutramine

12.3 g racemic sibutramine was dissolved in ethyl acetate (85 mL), and asolution of 21.7 g L-dibenzyltartaric acid (“L-DBTA”) in ethyl acetate(85 mL) was added thereto. The reaction mixture was heated to reflux andcooled to room temperature. The white precipitate was collected (ee ofsalt is ca 85%). The solid was then suspended in 220 mL ethyl acetateand heated at reflux for 30 minutes. The solid was collected to give>95%ee. The salt was further crystallized in isopropyl alcohol (450 mL) togive 11.3 g of salt with>99.3% ee. (−)-Sibutramine L-DBTA (yield 76%).Free base was obtained by treatment of the salt with saturated aqueousNaHCO₃ and extracted with chloroform. The (−)-sibutramine HCl salt wasobtained with treatment of the free base with HCl/Et₂O as describedabove. Optical rotation of the HCl salt was [α]=3.15 (c=0.9, H₂O), ¹HNMR ¹³C (CD₃OD), and M⁺=279. The resolution mother liquor was treatedwith NaOH to give the partially enriched (+)-sibutramine and was thentreated with D-DBTA as described above to give (+)-sibutramine-D-DBTAsalt with>99.3% ee. The sibutramine enantiomers were characterized by ¹Hand ¹³C NMR: M⁺=279. The material was also characterized by HPLC andChiral HPLC.

5.2. Example 2

DESMETHYLSIBUTRAMINE FROM SIBUTRAMINE

(−)-Sibutramine (1.25 g) was dissolved in toluene (90 mL) anddiethylazo-dicarboxylate (“DEAD”) was added (0.8 g, 1.1 eq). Thereaction mixture was heated at 50° C. for 6 hours, and 0.8 g DEAD wasadded. The reaction was heated at 50° C. for another 6 hours, cooled toroom temperature and the toluene was removed under vacuum. The residuewas suspend in 45 mL of ethanol and 45 mL of saturated aqueous NH₄Cl.The reaction mixture was heated under reflux for 3 hours. The reactionmixture was cooled to room temperature and concentrated to removeethanol. Aqueous NaHCO₃ was added until the concentrate was basic. Thebasic concentrate was extracted with dichloromethane, (3×50 mL). Theextracts were combined, dried with sodium sulfate, filtered andconcentrated to give a crude product. Flash column chromatography (SiO₂)(ethyl acetate/TEA 99:1) gave 0.43 g product. It was characterized by ¹Hand ¹³C NMR, M⁺=266, and optical rotation [α]=−10.6, c=3.3, (CHCl₃.) Theother enantiomer and racemate were prepared similarly and the isomer wascharacterized as the (−)-isomer.

Synthesis of desmethylsibutramine hydrochloride isomers

To a solution of (−)-desmethylsibutramine (0.78 g) in ethyl acetate (5mL) at 0° C. was added HCl/diethyl ether (1 M, 5 mL). The reactionmixture was stirred for 1 hour and the solid was collected byfiltration. The solid was then dried to give 0.68 g white solid. Theproduct was characterized by ¹H and ¹³C NMR (DMSO-d₆), and a chemicalpurity of>99% was determined by HPLC. [α]=−5° (c=0.5, H₂O). The racemateand the other enantiomer were prepared and characterized in the sameway.

5.3. Example 3

(R/S)-DESMETHYLSIBUTRAMINE

Preparation of 1-(4-Chlorophenyl)-1-cyclobutyl carboxaldehyde

Diisobutylaluminum hydride (DIBAL-H) (87 mL, 1M in THF, 87.0 mmol) wasadded to a solution of 1-(4-chlorophenyl) cyclobutanecarbonitrile (CCBC;10 g, 52.1 mmol) maintained at −20° C. The resulting mixture was stirredfor 4-5 hours at 0° C. and then poured into a 10% aqueous citric acidsolution and diluted with 200 mL MTBE. The mixture was stirred at roomtemperature for 3-4 hours. The aqueous layer was washed with MTBE (1×50mL) and the combined organic layers were dried over MgSO₄ andconcentrated to give 9 g (89%) of the above-captioned aldehyde as anoil. ¹H NMR (CDCl₃) δ 9.52 (s, 1H), 7.35-7.06 (m, 4H), 2.77-2.68 (m,2H), 2.43-2.32 9m, 2H), 2.06-1.89 (m, 2H). ¹³ C NMR δ 198.9, 139.4,132.9, 128.9, 127.8, 57.1, 28.3, 15.8.

Preparation of 1-(4-chlorophenyl)-1-cyclobutyl N-methylcarbaimine

A mixture of 1-(4-chlorophenyl)-1-cyclobutyl carboxaldehyde (3 g, 15.4mmol) and methyl amine (12 mL, 40% aqueous w/w, 154 mmol) was stirred atroom temperature for 18-40 hours. The reaction mixture was extractedwith MTBE (2×50 mL). The combined organic layers were dried over K₂CO₃and concentrated to give 2.5 g (78%) of the above-captioned imine as anoil. ¹H NMR (CDCl₃) δ 7.65 (m, 1H), 7.33-7.11 (m, 4H), 3.34 (s,3H),2.69-2.44 (m, 2H), 2.44-2.34 (m, 2H), 2.09-1.84 (m, 2H); ¹³C NMR δ168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 47.6, 30.6, 15.8.

Preparation of1-(4-chlorophenyl)-N-methyl-2-(2-methylpropyl)-cyclobutanamethamine

To a solution of 1-(4-chlorophenyl)-1-cyclobutyl N-methylcarbaimine(0.5g, 2.4 mmol) cooled to 0° C. was added BF₃.OEt₂ (0.34 g, 2.4 mmol).The mixture was stirred for 1 hour and then cooled to −78° C. At thistemperature, isobutyl magnesium bromide (2.5 mL, 2M in ether, 5 mmol)was added to form a mixture which was stirred at −78° C. for 2 hours andthen warmed to room temperature and stirred overnight. The reaction wasquenched with saturated NaHCO₃ solution (10 mL) and diluted with MTBE(15 mL). The organic layer was dried over MgSO₄, concentrated, andpurified by silicagel chromatography (eluting with 1% NEt₃ in ethylacetate) to give 380 mg of the above captioned amine as an oil. ¹H NMR(CDCl₃) δ 7.35-7.19 (m, 4H), 2.65-2.74 (m, 1H), 2.57 (s, 3H), 2.20-2.56(m, 5H), 1.60-2.00 (m, 3H), 1.20-1.00 (m, 2H), 0.95-0.90 (m, 6H),0.67-0.60 (m. 1H). ¹³C NMR δ 144.7, 131.3, 129.1, 127.4, 65.5, 51.7,41.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0, 16.3.

5.4. Example 4

(R/S)-DESMETHYLSIBUTRAMINE-HCL

Toluene (150 mL) and a solution of CCBC (50.0 g, 261 mmol) in toluene(45 mL) were added to a solution of isobutyl magnesium bromide in THF(392 mL, 1M in THF, 392 mmol). The resulting mixture was distilled untilthe internal temperature reached 105-110° C. and was then refluxed atthis temperature range for 2-4 hours. The reaction mixture was thencooled to 0° C. and quenched with methanol (295 mL). NaBH₄ (11 g, 339mmol) was added portion-wise over 15 minutes to the reaction mixture at0° C. After stirring for 15 minutes, the reaction mixture wastransferred into a 2N aqueous HCl solution (365 mL). The organic phasewas distilled until the internal temperature reached 105° C., and wasthen allowed to cool to room temperature. Formic acid (24 g, 522 mmol)was then added to the reaction mixture, which was then heated to reflux(92-96° C.) for 6-8 hours after which time the reaction mixture wasdistilled until the internal temperature reached 108° C. The mixture wasthen cooled to 10° C. and BH₃.THF (653 mL, 1.0 M, 653 mmol) was added.The resulting mixture was heated to reflux (69° C.) for 15 hours. Themixture was then cooled to 5° C., combined with methanol (105 mL), andrefluxed again for 45 minutes. The reaction mixture was distilled untilthe internal temperature reached 116° C., and then allowed to cool to25° C. Hydrochloric acid in MTBE (373 g, 18 wt % of HCl, 1840 mmol) wasthen added to the mixture to provide a white slurry which was refluxedfor 1 hour and then filtered to give 62.3 g (79.0%) of (R/S)-DMS.HCl.NMR (CDCl₃): ¹H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b, 2H), 1.65-2.14 (b,4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H),9.0-9.5 (b, 2H). ¹³C (d): 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2,35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.5. Example 5

(R)-DESMETHYLSIBUTRAMINE-HCL

Formation of (R)-Mandelate Salt of (R)-DMS

(R/S)-Desmethylsibutramine HCl ((R/S)-DMS.HCl) (60 g) was added to ethylacetate (300 mL) and the resulting mixture was cooled to 0° C. AqueousNaOH (1.5 N, 300 mL) was then added to the reaction mixture, which wasthen stirred for 30 minutes. The organic phase was separated, washedwith water (150 mL), and concentrated. (R)-Mandelic acid (30.3 g), ethylacetate (510 mL total), and heptane (204 mL) were then added to theconcentrated organic phase. The resulting mixture was then heated toreflux for 1 hour, after which time it was cooled to 20-23° C.Filtration of the resulting slurry yielded 36.4 g (43.8%) of(R)-desmethylsibutramine-(R)-mandelate ((R)-DMS.(R)-MA; 95.5% ee).

Enrichment of (R)-DMS.(R)-MA

A mixture of (R)-DMS.(R)-MA (30 g, 0.072 mol), ethyl acetate (230 mL),and heptane (230 mL) was heated to reflux for 1 hour. After cooling to20-23° C., the product was filtered and dried to give 29.6 g (98%) of(R)-DMS.(R)-MA (99.9% ee).

Formation of HCl Salt of (R)-DMS

A mixture of (R)-DMS.(R)-MA (50 g, 0.12 mol), NaOH (100 ml, 3.0 N), andtoluene (500 mL) was stirred for 30 minutes. The organic phase waswashed with water (200 mL), concentrated to about 300 mL, and cooled toroom temperature. HCl/MTBE (100 mL, 14%, 0.34 mol) was then slowly addedto the mixture to form (R)-DMS.HCl. After stirring for 30 minutes, theslurry was filtered and the resulting wet cake was washed two times withMTBE and dried to give 34.5 g (95.5%) of (R)-DMS.HCl (99.9% ee; 99.9%chemically pure by NMR). NMR (CDCl₃): ¹H (δ), 0.85-1.1 (m, 6H), 1.24-1.5(b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6(b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H), ¹³C (δ): 15.5, 21.4, 23.5,24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.6. Example 6

(S)-DESMETHYLSIBUTRAMINE.HCL

Formation of (S)-Mandelate Salt of (S)-DMS

A mixture of (R/S)-DMS.HCl (5.0 g), NaOH (1.5N, 20 mL) and ethyl acetate(50 mL) was stirred for 30 minutes. The organic phase was washed withwater (20 mL) and concentrated to give desmethylsibutramine free base(4.2 g, 96%).

Desmethylsibutramine free base (1.1 g, 4.1 mmol) was combined with(S)-mandelic acid (0.62 g, 4.1 mmol), ethyl acetate (11 mL), and heptane(4.4 mL). The resulting mixture was heated to reflux for 30 minutes andcooled to 20-23° C. Filtration of the resulting slurry gave 0.76 g of(S)-desmethylsibutramine.(S)-mandelate salt ((S)-DMS.(S)-MA) (96% ee).

Enrichment of (S)-DMS.(S)-MA

A mixture of (S)-Desmethylsibutramine.(S)-mandelate (0.76 g), ethylacetate (5 mL), and heptane (5 mL) was heated to reflux for 1 hour.After cooling to 20-23° C., the product was filtered and dried to give0.72 g (95%) of (S)-DMS.(S)-MA (99.9% ee).

Recovery of (S)-Mandelate Salt of (S)-DMS from Mother Liquor of(S)-DMS.(R)-MA

A solution of (S)-DMS.(R)-MA in ethyl acetate-heptane (67% ee motherliquor) was charged with NaOH (3N, 400 mL) and the reaction mixture wasstirred for 30 minutes. The organic phase was washed with water andconcentrated. The resulting residue (130 g, 0.49 mol and 67% ee) wascharged with (S)-mandelic acid (28.5 g, 0.49 mol), ethyl acetate (1400mL), and heptane (580 mL). The mixture was heated to reflux for 1 hourand then slowly cooled to room temperature. The resulting slurry wasfiltered and dried to give 147 g (86% based on (S)-isomer) of(S)-DMS.(S)-MA (99.9% ee).

Formation of HCl Salt of (S)-DMS

(S)-Desmethylsibutramine.(S)-mandelate (20 g, 0.048 mol) was added to amixture of NaOH (60 ml, 3.0 N) and toluene (200 mL). The mixture wasstirred for 30 minutes and the organic phase was then washed with water(100 mL), concentrated to about 100 mL, and cooled to room temperature.Hydrochloric acid in MTBE (40 mL, 14%, 0.13 mol) was then added slowlyto the mixture to form (S)-DMS.HCl. After stirring for 30 minutes, theslurry was filtered and the resulting wet cake was washed two times withMTBE and dried to give 14 g (96.7%) of (S)-DMS.(L)-MA (99.9% ee; 99.9%chemical purity). NMR (CDCl₃): ¹H (δ), 0.84-1.1 (m, 6H), 1.25-1.5 (b,2H), 1.65-2.15 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (b,1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). ¹³C (δ): 15.5, 21.4, 23.5, 24.7,31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.7. Example 7

(R/S)-DIDESMETHYLSIBUTRAMINE

A 1 L three-necked round bottom flask was charged with isobutylmagnesium bromide (200 mL, 2.0 M in diethyl ether) and toluene (159 mL)and the resulting mixture was distilled to remove most of the ether.After the mixture was cooled to 20° C., CCBC (50.0 g ) in toluene (45mL) was added, and resulting mixture was refluxed for 2-4 hours. Thereaction mixture was then cooled to 0° C. and methanol (300 mL) wasadded to it, followed slowly by NaBH₄ (11 g). The resulting mixture wasthen stirred at about 0-10° C. for 15 minutes. The reaction mixture wasthen added slowly to an aqueous HCl solution (365 mL, 2N) kept at 0° C.,and the resulting mixture was warmed to room temperature with continualstirring. After separation of the organic phase, the aqueous phase waswashed with toluene (200 mL). The combined organic phases were washedwith water (200 mL) and concentrated to give (R/S)-DDMS (55 g, 85%). NMR(CDCl₃): ¹H (δ), 0.6-0.8 (m, 1H), 0.8-1.0 (m, 6H), 1.1-1.3 (m, 1H),1.6-2.6 (m, 7H), 3.0-3.3 (m, 1H), 7.0-7.6 (m, 4H), ¹³C (δ): 15.4, 21.5,24.3, 24.7, 31.5, 31.9, 41.1, 50.73, 56.3, 127.7, 129, 131.6, 144.2.

5.8. Example 8

(R/S)-DIDESMETHYLSIBUTRAMINE.(D)-TARTRATE

A mixture of racemic didesmethylsibutramine (15.3 g ) and toluene (160mL) was heated to 70-80° C. and (D)-tartaric acid (9.1 g) in water (20mL) and acetone (10 mL) was added slowly. The resulting mixture wasrefluxed for 30 minutes, after which the water and acetone were removedby distillation. The resulting mixture was cooled to room temperature toprovide a slurry which was then filtered. The resulting wet cake waswashed two times with MTBE (20 mL×2) and dried to yield(R/S)-DDMS.(D)-TA (22.5 g, 98%). NMR (DMSO): ¹H (δ), 0.6-0.92 (m, 6H),0.92-1.1 (m, 1H), 1.1-1.3 (m, 1H), 1.5-1.8 (m, 2H), 1.8-2.1 (m, 1H,2.1-2.4 (m, 3H), 2.4-2.6 (m, 1H), 3.4-3.6 (m, 1H), 3.9-4.2 (s, 2H),6.4-7.2 (b, 6H, OH, COOH and NH₂), 7.3-7.6 (m, 4H). ¹³C (δ): 15.5, 2.1,23.3, 23.7, 31.5, 31.8, 37.7, 39.7, 54.5, 72.1, 128, 129.7, 131.3,142.2, 174.6.

5.9. Example 9

(R)-DIDESMETHYLSIBUTRAMINE.(D)-TARTRATE

Resolution from Didesmethylsibutramine Free Base

A mixture of (R/S)-didesmethylsibutramine (20.3 g),acetone/water/methanol (350 mL, 1:0.13:0.7, v:v:v), and (D)-tartaricacid (12.1 g) were added to a 500 mL three-necked round bottom. Thereaction mixture was heated to reflux for 30 minutes and then cooled to45° C. The reaction mixture was then seeded with (R)-DDMS.(D)-TA (10 mg;99.6% ee) and stirred at 40-45° C. for 30 minutes. The mixture was thencooled to room temperature and stirred for 1 hour. The resulting slurrywas then filtered and the wet cake was washed with cold acetone/waterand dried to give 10.3 g (33%) of (R)-DDMS.(D)-TA (90% ee).

Resolution from (R/S)-Didesmethylsibutramine.(D)-tartrate

A mixture of (R/S)-didesmethylsibutramine.(D)-TA (5.0 g) in acetone (50mL), water (6.7 mL), and methanol (3.3 mL) was refluxed for 30 minutes.The mixture was then cooled to room temperature and the resulting slurrywas filtered to provide a wet cake which was then washed with coldacetone and dried to give (R)-DDMS.(D)-TA (1.4 g, 28%; 92% ee).

Enrichment of (D)-Tartrate Salt of (R)-DDMS

A mixture of (R)-DDMS.(D)-TA (25 g, 92% ee) andacetonitrile/water/ethanol (300 mL:65 mL:30 mL) was refluxed for 1 hour.The mixture was then cooled to room temperature to provide a slurrywhich was filtered and dried to give (R)-DDMS.(D)-TA (18 g, 71.3%; 99.7%ee; and 99.91% chemical purity). NMR (DMSO-d₆): ¹H (δ), 0.7-0.9 (m,6H),0.9-1.05 (t, 1H), 1.1-1.24 (b, 1H), 1.5-1.8 (b, 2H), 1.8-2.02 (b, 1H),2.1-2.4 (3, 3H), 2.4-2.6 (b, 1H), 3.5 (m, 1H), 4.0 (s, 2H), 7.1-7.6 (m,4H, with 6H from NH₂, OH and COOH). ¹³C (δ): 15.4, 21.5, 22.0, 22.2,32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

5.10. Example 10

(S)-DIDESMETHYLSIBUTRAMINE.(L)-TARTRATE

Formation of (L)-Tartrate Salt of (S)-DDMS

(R/S) Didesmethylsibutramine (20.5 g), acetone/water/methanol (350 mL,1:0.13:0.7, v:v:v) and (L)-tartaric acid (12.2g) were added to a 500 mLthree-necked round bottom flask. The mixture was heated to reflux for 30minutes and then cooled to 45° C. The reaction mixture was then seededwith (S)-DDMS.(L)-TA (10 mg and 99.7% ee) and stirred at 40-45° C. for30 minutes. The mixture was cooled to room temperature and stirred for 1hour. The resulting slurry was filtered to provide a wet cake, which waswashed with cold acetone/water and dried to give 10.8 g (33.4%) of(S)-DDMS.(L)-TA (89.7% ee).

Preparation of (L)-Tartrate Salt of (S)-DDMS from

Mother Liquor of (R)-DDMS.(D)-TA

A solution of DDMS tartrate in acetone/water/methanol (mother liquor of(R)-DDMS.(D)-TA) was concentrated to remove acetone and methanol. Theresidue was treated with aqueous NaOH (3N, 150 mL) and extracted withethyl acetate. The organic phase was washed with water (100 mL) andconcentrated to give didesmethylsibutramine free base (45 g, 0.18 moland 36% ee of (S)-isomer). The free amine was charged with (L)-tartaricacid (53.6 g, 0.35 mol), acetone (600 mL), water (80 mL), and methanol(40 mL). The mixture was heated to reflux for 1 hour and then cooled toroom temperature. The resulting slurry was filtered to provide a wetcake, which was then washed with cold acetone/water two times to give26.7 g (56% based on (S)-didesmethylsibutramine) of (S)-DDMS.(L)-TA (96%ee).

Enrichment of (S)-DDMS.(L)-TA

A mixture of(S)-DDMS.(L)-TA (26.7 g) in acetonitrile/water (475 mL;1:0.2, v:v) was refluxed for 1 hour and then cooled to room temperature.The resulting slurry was filtered and dried to give 17.4 g (65%) of(S)-DDMS.(L)-TA (99.9% ee; 99.94% chemical purity). NMR (DMSO-d6): ¹H(δ), 0.7-0.9 (m, 6H), 0.9-1.05 (m, 1H), 1.1-1.3 (b, 1H), 1.52-1.8 (b,2H), 1.84-2.05 (b, 1H), 2.15-2.4 (b, 3H), 2.4-2.6 (b, 1H), 3.65-3.58 (m,1H), 4.0 (s, 2H), 6.7-7.3 (b, 6H from NH₂, OH and COOH) 7.1-7.6 (m, 4H).¹³C (δ): 15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8,128.8, 130.0, 132.0, 143.0, 175.5.

5.11. Example 11

DETERMINATION OF POTENCY AND SPECIFICITY

A pharmacologic study is conducted to determine the relative potency,comparative efficacy, binding affinity, and toxicity of the racemicmixture of sibutramine, its enantiomers, the metabolites of sibutramine,and their enantiomers. The profile of relative specificity of monoaminereuptake inhibition is determined from the compounds' inhibition ofnorepinephrine (NE) reuptake in brain tissue with that of the inhibitionof dopamine (DA) and serotonin (5-HT) reuptake.

High-affinity uptake of the ³H-radiomonoamines is studied insynaptosomal preparations prepared from rat corpus striatum (forinhibition of DA reuptake) and cerebral cortex (for SHT and NE) usingmethods published by Kula et al., Life Sciences 34(26): 2567-2575, 1984,and Baldessarini et al., Life Sciences 39:1765-1777, 1986. Tissues arefreshly dissected on ice and weighed. Following homogenization by hand(14 strokes in 10-35 vols of ice-cold isotonic 0.32M sucrose, containingnialamide, 34 μM) in a Teflon-on-glass homogenizer, the tissue iscentrifuged for ten minutes at 900 ×g; the supernatant “solution” thatresults contains synaptosomes that are used without further treatment.Each assay tube contains 50 μL of the cerebral homogenate,radiolabelled-³H-monoamine, and the test compound (e.g., the puresibutramine enantiomers, the racemate, and appropriate standards) in afreshly prepared physiologic buffer solution with a final volume of 0.5mL. Tissues are preincubated for 15 minutes at 37° C. before the assay.Tubes are held on ice until the start of incubation, which is initiatedby adding ³H-amine to provide a final concentration of 0.1 μM. Tubes areincubated at 37° C. for 10 minutes with ³H-DA (26 Ci/mmol) and for 20minutes with ³H-5HT (about 20 Ci/mmol) and ³H-NE (about 20 Ci/mmol). Thespecific activity of the radiomonoamine will vary with availablematerial and is not critical. The reaction is terminated by immersion inice and dilution with 3 mL of ice cold isotonic saline solutioncontaining 20 mM TRIS buffer (pH 7.0). These solutions are filteredthrough cellulose ester microfilters, followed by washing with two 3 mLvolumes of the same buffer. The filter is then counted for³H-radioactivity in 3.5 mL of Polyfluor at about 50% efficiency fortritium. Blanks (either incubated at 0° C. or incubated with specific,known uptake inhibitors of DA [GRB-12909, 10 μM], 5HT- [zimelidine 10μM], or of NE [desipramine 10 μM]) are usually indistinguishable fromassays performed without tissue and average 2-3% of total CPM.

Comparison of the amounts of ³H-radioactivity retained on the filtersprovides an indication of the relative abilities of the pure enantiomersand racemic mixture of sibutramine (and of known DA, 5-HT, and NEreuptake inhibitors) to block the reuptake of these monoamines in thosetissues. This information is useful in gauging the relative potency andefficacy of compounds of the invention (e.g., dopamine reuptakeinhibitors, such as a racemic or optically pure sibutramine metabolite,and 5-HT₃ antagonists).

The acute toxicities of the compounds of the invention are determined instudies in which rats are administered progressively higher doses(mg/kg) of the pure isomers or racemate. That lethal dose which, whenadministered orally, causes death of 50% of the test animals, isreported as the LD₅₀. Comparison of LD₅₀ values for the enantiomers andracemate provides a measure of the relative toxicity of thecompositions.

5.12. Example 12

BINDING AFFINITIES

The binding affinities of racemic and optically pure sibutramine ((±)-,(+)-, and (−)-sibutramine), desmethylsibutramine ((±)-, (+)-, and(−)-desMe), and didesmethylsibutramine ((±)-, (+)-, and (−)-didesMe)were determined at the nonselective muscarinic receptor and theserotonin (5-HT) uptake site from rat cerebral cortex, the humanrecombinant norepinephrine (NE) uptake site, and the β₃-receptor fromrat adipose tissue. Compounds were tested initially at 10 μm induplicate, and if≧50% inhibition of specific binding was observed, theywere tested further at 10 different concentrations in duplicate in orderto obtain full competition curves. IC₅₀ values (concentration requiredto inhibit 50% specific binding) were then determined by nonlinearregression analysis of the curves and tabulated below.

Binding IC₅₀ Values (nM) Muscarinic NE 5-HT 5-HT Selectivity CompoundReceptor Uptake Uptake (NE/5-HT) (±)-Sibutramine 2,650 350 2,800 1,200(+)-Sibutramine 4,010 110 2,100 650 (−)-Sibutramine 3,020 2,500 4,9001,500 (±)-desMe 1,170 10 21 19 (+)-desMe — 4 44 12 (−)-desMe 654 8709,200 180 (±)-didesMe — 16 63/14 39/26 (+)-didesMe — 13 140 8.9(−)-didesMe — 6.2 4,300 12 Atropine 0.31 — — — GBR 1909 — — — 5.6/2.6Imipramine — — 145/32 — Protriptyline — 3.6/0.9 — — Zimelidine — — 129 —

None of the compounds showed more than 15% inhibition of binding at theβ₃-receptor, and affinity for the muscarinic site was weak compared toatropine. Further, binding to the NE and 5-HT uptake sites was orders ofmagnitude less than that of the standards.

The above data, which was generated as described above in Example 13,shows that (+)-desmethylsibutramine and (+)-didesmethylsibutramine arepotent inhibitors of NE uptake and 5-HT uptake, but have negligibleactivity at muscarinic receptors.

5.13. Example 13

ORAL FORMULATION

Hard gelatin capsule dosage forms that are lactose-free comprisingsibutramine metabolites can be prepared using the following ingredients:

Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or optically5.0 10.0 20.0 pure sibutramine metabolite Microcrystalline 90.0 90.090.0 Cellulose Pre-gelatinized 100.3 97.8 82.8 Starch Croscarmellose 7.07.0 7.0 Magnesium 0.2 0.2 0.2 Stearate

The racemic or optically pure sibutramine metabolite is sieved andblended with the excipients listed. The mixture is filled into suitablysized two-piece hard gelatin capsules using suitable machinery andmethods well known in the art. See, e.g., Remington's PharmaceuticalSciences, 16th or 18th Editions, each incorporated herein in itsentirety by reference. Other doses can be prepared by altering the fillweight and, if necessary, changing the capsule size to suit. Any of thestable, non-lactose hard gelatin capsule formulations above can beformed.

Compressed tablet dosage forms of sibutramine metabolites can beprepared using the following ingredients:

Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or optically5.0 10.0 20.0 pure sibutramine metabolite Microcrystalline 90.0 90.090.0 Cellulose Pre-gelatinized 100.3 97.8 82.8 Starch Croscarmellose 7.07.0 7.0 Magnesium 0.2 0.2 0.2 Stearate

The racemic or optically pure sibutramine metabolite is sieved through asuitable sieve and blended with the non-lactose excipients until auniform blend is formed. The dry blend is screened and blended with themagnesium stearate. The resulting powder blend is then compressed intotablets of desired shape and size. Tablets of other strengths can beprepared by altering the ratio of the active ingredient to theexcipient(s) or modifying the table weight.

The embodiments of the invention described above are intended to bemerely exemplary and those skilled in the art will recognize, or be ableto ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A compound of the formula:

and pharmaceutically acceptable salts, solvates and clathrates thereof,wherein R is alkyl.
 2. The compound of claim 1 wherein alkyl is C₁-C₆alkyl.
 3. The compound of claim 2 wherein the C₁-C₆ alkyl is methyl. 4.A method of preparing a compound of Formula 2:

which comprises contacting cyclobutanecarbonitrile withdiisobutylaluminum hydride to form an intermediate; and reacting theintermediate with CH₃NH₂ at a temperature and for a time sufficient toform the compound of Formula
 2. 5. A method of preparing racemic oroptically pure desmethylsibutramine which comprises contacting acompound of Formula 2 with a compound of the formula AMX, wherein A isaryl, alkyl, or aralkyl, M is Li or Mg, and X is a halogen atom.